D-homoestra-1,3,5(10)-trienes and 1,3,5(10)9(11)-tetraenes

ABSTRACT

THIS INVENTION RELATES TO NOVEL STEROID-LIKE COMPOUNDS, A METHOD FOR SYNTHEISIZING SAID COMPOUNDS AND TO THE USE THEREOF AS ESTROGENIC AGENTS IN THE TREATMENT OF LABORATORY AND DOMESTIC ANIMALS.

United States Patent Office 3,565,958 Patented Feb. 23, 1971 3,565,958D-HOMOESTRA-1,3,5(10)-TRIENES AND 1,3,5(10)9(11)-TETRAENES Marinus Los,20 Lawnside Drive,

Trenton, NJ. 08638 No Drawing. Filed Feb. 27, 1968, Ser. No. 708,498Int. Cl. C07c 49/76, 49/82 US. Cl. 260586 8 Claims ABSTRACT OF THEDISCLOSURE This invention relates to novel steroid-like compounds, amethod for synthesizing said compounds and to the use thereof asestrogenic agents in the treatment of laboratory and domestic animals.

BRIEF SUMMARY OF THE INVENTION The present invention relates tosteroid-like compounds having a formula selected from the groupconsisting of (A):

where R is a member selected from the group consisting of t-butoxy,ethylenedioxy, tetrahydropyranyloxy, oxygen and hydroxyl; X is selectedfrom the group consisting of HOCH= and H and Y is selected from thegroup consisting of 7 l 2 CH2 CH CH1, CH 2 II o H HO /CH CH3O /CHz andCH0 wherein R is as described above, R is selected from the groupconsisting of H and loweralkyl (C -C and Z is selected from the groupconsisting of CH OH and OCHa compounds within the scope of these genericformulas A and B are hereinafter disclosed in Sheets I and II of thesynthesis diagrams. They include Formulae II, III and V through XVIIreferred to in said diagram and in the specification and examples.

where R is selected from the group consisting of oxygen, and hydroxyland hydrogen is either cis or trans to the potential C methyl describedhereinafter. Compounds of the following Formulae D through G aredirected to Formulae XVIII through XXXI on the sheets II and III of thesynthesiss diagrams hereinafter.

where R, is selected from the group consisting of oxygen, hydroxyl andacetoxy.

where R is as described above.

where the C hydrogen is cis or trans to the C methyl group.

fiw

omo-

where Q is selected from the group consisting of C--CECH n and hydrogenis cis or trans to the C methyl group.

PREFERRED EMBODIMENT OF THE INVENTION and tetrahydropyranyloxy R ishydrogen or lower alkyl, such as methyl, ethyl, propyl, isopropyl or thelike and R is oxygen or hydroxyl.

Briefly, the enedione having the formula can be converted to the FormulaVI compound wherein R is ethylenedioxy by treatment thereof with excessethylene glycol and p-toluenesulfonic acid in an inert solvent such asbenzene at an elevated temperature. Reaction of the thus formedmonoketal with ethylformate and an alkali metal methoxide gives thehydroxymethylene ketone which, when treated with N-methylaniline yieldsthe Formula I compound wherein R is ethylenedioxy.

Treatment of the above-identified enedione with an alkali metalborohydride in the presence of a lower a1- kanol gives the naphthalenonecorresponding to Formula IV wherein R is hydroxyl. The alcohol is thendissolved in methylene chloride and the solution treated withisobutylene in the presence of an acid catalyst to obtain the Formula IVcompound wherein R is t-butoxy. The corresponding tetrahydropyranyloxycompound is made from the alcohol by dissolving the same intetrahydrofuran and treating the formed solution with the dihydropyrancontaining phosphorus oxychloride. Preparation of Formula I compoundswherein R is t-butoxy or tetrahydropyranyloxy is then achieved in thesame manner as described above for the Formula I compound in which R isethylenedioxy. This involves preparation of the formyl compound andtreatment thereof with N- methylaniline.

The allyl compounds (II) are obtained by alkylation of theN-methylanilinomethylene Compound (I) with an allyl halide such as allylbromide. Hydrolysis of (II) under strongly basic conditions then givesthe desired unblocked ketone (III) which, when ozonized, yields byselective cleavage of the allyl double bond the corresponding aldehyde(VI). The unblocked ketone (H) can also be obtained directly from theenone (IV) by treatment of (IV) with a strong base such as potassium tbutoxide or sodium hydride in an inert solvent such as t-butanol ordimethoxyethane followed by allyl bromide at an elevated temperature.Reaction of the thus formed product (HI) in tetrahydrofuran with analkali metal chlorate and osmium tetroxide gives the hemiketal (V) whichis converted to the aldehyde (VI) by reaction with an alkali metalperiodate and further treatment of the aldehyde (VI) withm-methoxyphenyl magnesium bromide gives the hemiketal (VII) (R =H) ingood yield.

The hemiketal (VII) is also prepared from the starting material (I) bythe route involving reaction of the anion of (I) with m-methoxyphenacylbromide, preferably at about 0 C. to obtain the anilino compound (VIII)which, on hydroxysis in strong base gives the unblocked ketone (X). Thereaction is preferably run at an elevated temperature in a loweralkylene glycol. If the reaction is terminated after a short period ofreflux about 1 to 3 hours, a major portion of the product obtained willbe the formyl compound (IX), however, if the reaction is run forapproximately 6 hours, the unblocked ketone (X) is obtained in highyield. Reduction of this latter compound with hydrogen in acetic acidand a catalyst such as palladium gives the ketone (XI). The reaction ispreferably run at an elevated temperature between about 50 and C. and ata super atmospheric pressure. Acid hydrolysis of the thus formed product(XI) yields the diketone or ketoalcohol (XV). The ketone (XI) may alsobe obtained from the hemiketal (VII) by reduction of the same withhydrogen and a palladium catalyst in acetic acid. In addition to theprevious route described for the preparation of (VII), such product canbe obtained by catalytic reduction of the diketone (X). When thisproduct (VII) is then hydrolyzed with aqueous acetic acid at an elevatedtemperature the hemiketal (XII) is formed. When (VII) (Rm-butoxy ortetrahydropyranyloxy R =H, CH or C H is hydrolyzed by mineral acid, then(XVI) is the product. When the compound (XII) is then subject totreatment with hot acetic acid-acetic anhydride mixture the diketone(XIII) is formed. This product is also obtained when (VII)(R=ethylenodixy and R is H or CH is treated with acetic acid and aceticanhydride giving the acetoxyketone which is hydrolyzed to the diketone(XIII) in aqueous acetic acid. Conversion of the diketone (XIII) to thetrans-styrene (XIV) is accomplished by reaction thereof with a strongacid such as p-toluene sulfonic acid at an elevated temperature in aninert solvent. Hydrogenation of the trans-styrene (XIV) yields theenedione (XV) (R =O) identical with that formed by acid hydrolysis of(XI) (R=ethylenedioxy). When the hemiketal (XVI) is reduced withhydrogen in the presence of a catalyst (XV) (RFhydroxyl) is obtained.

The enedione XV (R oxygen) is then reduced with sodium borohydride tothe unsaturated keto alcohol (XVII). Further reduction of (XVII) withhydrogen in the presence of a paladium catalyst yields the keto alcohol(XVIII) which is readily oxidized to trans-dione (XIX) by mild oxidationwith I ones reagent. Cyclization of (XIX) by mineral acid at an elevatedtemperature gives the D-homo steroid (XX). Reaction of (XX) withacetylene in the presence of a strong base in an inert solvent thenyields the estrogenically active ethynyl alcohol (XXXI). Catalyticreduction of ketone (XX) using hydrogen and a palladium catalyst yieldsthe ketone (XXIX) which when treated with acetylene in the presence of astrong base gives the estrogenically active ethynyl alcohol (XXX).

This estrogenically active compound (XXX) can also be obtained from thediketone (XV) by a process involving treatment thereof with a strongmineral acid at an elevated temperature. The reaction is preferablycarried out in a lower alkanol and gives the D-homo ketone (XXI) whichis readily reduced to the corresponding alcohol (XXII) using an alkalimetal borohydride. Treatment of the. thus formed product with aceticanhydride then yields the diene (XIII) which is catalytically reduced tothe D-homo acetate (XXIV). Refluxing of the prepared product in a loweralcohol in the presence of (I) Sheet: I CH3 CH3 (v i) (IX) (X) -J R l RR R .9 CGHFN- on I GEES-N- OH HOCH l I I f e I199 Q3 0 o I 0 l 0 l El- 1CK: v Ch' O CHa cuao K I R (I1) 0 O \0 H c n -n-cit 0 I J V R V R (v1) R(VII \I/ R (III) I l HO R'O 0 0 i I CH0 To xv V R i L 0c v) I 0 XII T0XVI R t--bu.'uo;:3r, cthylenedioxy or tetrahydropyranyloxy L V R: H orloweralkyl ins [from VII ,figom Y1]; from XI v v 0 (XII) (XVI) I OH HOo; i m I 0 o (XIII) OCHa V ciao 0 IV) OCOCHa 2 (Xv) To Sheet III Sheet:xvmhere R2 o or: (XXII) 0 (min) I I O (XXI) )ijK H L Q) i 0 v OCOCI CH3?CHGO J 3 (XXIII) V CH O I 3H 0 vOCOCHa O (xxvIII) GEE; (XVII) 3 (m) CH3v 0H H C530 J (xxv) OH (XXVI) Co 1 u i 01530 If 4 Sheet: Ii

From XX rom XXVI v From XX 0 (XXIX) I I cn H OH c CH J --CECI1'.

l (xxxI) i CH3 H C11 0 H The novel compounds of this inventionrepresented by (F) P Formulas A, B, C, and E set forth in the abovesummary, are useful as intermediates, in the synthesis of the estrogeniccompounds of the Formulas D, F, and G, depicted in said summary. H

As indicated compounds of the formulas: H R; 01130- wherein R is oxygen,hydroxyl or acetoxy, P is I OH r-05011 d CHaO an Q18 0 01-1 or OH (G) (3c--ozcn I W and I E or (3H H C-CECH 0 the C hydrogen is either cis ortrans to the C methyl group. These compounds have substantial estrogenicactivity in domestic and laboratory animals such as rats, guinea pigs,rabbits, sheep, swine and the like.

In the treatment of the smaller animals such as rabbits, guinea pigs andrats, generally about 0.225 to 10 mg. and preferably 0.50 to 10mg./head/day of a compound of the above formula is effective inobtaining an estrogenic response in said animals.

These estrogenically active compounds may be administered by injectionas a liquid formula described in Example 32 hereinafter, or they may beadministered as solids admixed with the feed or in the form of tablets,pills, capsules, powders or as liquids, emulsions, solutions orsuspensions using a conventional pharmaceutically acceptable carrier.

DETAILED DESCRIPTION The following examples describe in detail thepreparation of representative compounds within the scope of the presentinvention and illustrated structurally on the synthesis diagram.

EXAMPLE 1 Preparation of 4,4a,5,6,7,8-hexahydro-5fi-hydroxy-1,4a,8-dimethyl-2(3H)naphthalenone (IV-R hydrOxyl) A solution containing 58.4g. (0.304 mole) endione in 500 ml. absolute ethanol is cooled to withstirring. Then 1.3 sodium borohydride is added to the solution and at 15minute intervals, two more portions of 1.3 g. sodium borohydride isadded. Fifteen minutes after the final addition, the solution isacidified with acetic acid and then the solvents evaporated. The residueis dissolved in chloroform, the organic phase washed with water,saturated sodium bicarbonate solution, dried and evaporated. The residueis distilled and recrystallized from etherhexane and has melting point7980 C.

Calcd. for C H O (percent): C, 74.19; H, 9.34. Found (percent): C,74.17; H, 9.24.

EXAMPLE 2 Preparation of 5,6-tert-butoxy 4,4a,5,6,7,8 hexahydro-1,4aB-dimethyl 2(3H)naphthalenone (IV*R=tertiarybutoxy) To a solutioncontaining 4.0 g. (0.0206 mole) of the alcohol of Example 1 in 20 ml.dry methylene chloride at 20 C. in a pressure bottle is addedapproximately 20 ml. liquid isobutylene. Then 0.5 ml. catalyst (100%phosphoric acid saturated with boron trifluoride) is added, the pressurebottle closed and the mixture shaken at room temperature overnight. Thebottle is cooled to 20 C. opened and a stream of dry nitrogen passedthrough the solution to remove excess isobutylene. The residue isdiluted with methylene chloride and washed thoroughly with a saturatedsodium bicarbonate solution. The aqueous phase is re-extracted withmethylene chloride and the combined organic phase dried and evaporated.The products from a total of four such experiments were combined to give24.1 g. oil. This is dissolved in hexane and passed through a shortcolumn of neutral alumina. After evaporation of the solvent, the residueweighs 20.85 g. The t-butyl ether has boiling point 120122 C. at 0.3mm., N 1.5073.

EXAMPLE 3 Preparation of 4,4a,5,6,7,8-hexahydro-1,4ap-dimethyl-5B-[(tetrahydropyran 2 yl)-oxyl] -2(3H)naphthalenone(IV-R=tetrahydropyranyloxy) To a solution containing 1.94 g. (0.01 mole)of the alcohol (prepared in Example 1) in ml. dry tetrahydrofuran isadded 2.5 ml. of pure dihydropyran followed by 2 drops of phosphorusoxychloride. After standing at room temperature for 4 hours, thesolution is poured into saturated sodium bicarbonate solution, extractedwith ether and the ether extract dried and evaporated. The residueconsists of essentially pure tetrahydropyranyl ether. The infraredspectrum shows no residual hydroxyl group. Other strong acid catalystssuch as hydrochloric, sulfuric and p-toluenesulfonic acid may replacethe phosphorusoxychloride.

EXAMPLE 4 Preparation of 3',4',8',8'a-tetrahydro 5,8'a dimethylspiro[1,3 dioxolane-2,1f(2H)-naphthalen]-6'(7'H)- one (IV-R=ethylenedioxy) Toa mixture of 6 g. (3.13 mmoles) enedione (IV, R: =0), 10 ml. ethyleneglycol in 180 ml. benzene is added mg. p-toluenesulfonic acid. Thesolution is heated at reflux under a water separator for 2% hours. Thecold solution is diluted with ether and washed with sodium bicarbonatesolution, water and saturated brine. The residue is filtered through aplug of alumina in benzene and the solvent evaporated. Crystallizationof the residue from hexane at 0 gives 4.6 g. ketal (62.5%), meltingpoint 5355 C.

EXAMPLE 5 Preparation of 3,4,8',8 a-tetrahydro-7'-(hydroxymethylene)5',8'a dimethyl-spiro[1,3 dioxlane 2,1'(2'H- naphthalen] -6' (7'H) -oneIn a five liter B-necked flask equipped with stirrer, dropping funneland nitrogen inlet, there is placed 100 g. (1.85 moles) sodiummethoxide, 1,700 m1. benzene and through the dropping funnel, 265 ml.ethyl formate. After cooling in an ice-water bath, 127.4 g. (0.539 mole)ketal (prepared in Example 4) in 640 ml. benzene is added at 0 andstirred overnight at room temperature. The mixture is cooled to 0 and500 ml. of 2.5 M sodium dihydrogen phosphate solution added. A further500 ml. phosphate solution, 500 ml. water and 500 ml. benzene is addedand the aqueous phase separated. The organic phase is washed with water,dried and evaporated. The residue weighs 143 g. and has the abovestructure.

EXAMPLE 6 Preparation of 5,8-tert-butoxy-4,4a,5,6,7,8-hexahydro-3-(hydroxymethoxymethylene) 1,4a/3-dimethyl-2(3H)- naphthalenone In aflask equipped with stirrer, thermometer and dropping funnel withnitrogen inlet is placed 111 g. (2.06 mole) of sodium methoxide and1,900 ml. dry benzene. A nitrogen atmosphere is maintained throughoutthe reaction. Through the dropping funnel is then added 300 ml. ethylformate in a stream. The mixture is cooled to 12 C. and 150.5 g. (0.6mole) of crude t-butyl ether (prepared in Example 2) in 700 ml. drybenzene is added dropwise and the mixture stirred overnight. The organicphase is then extracted with water and 2 N sodium hydroxide. The aqueousphases are acidified with 2.5 M sodium dihydrogen phosphate andextracted with ether. The ether extract is washed with water, dried andevaporated to give 164.2 g. of oil. The formyl compound is crystallizedfrom n-propanol and has melting point 7677 C.

Calcd. for C H O (percent): C, 73.34; H, 9.41. Found (percent): C,73.26; H, 9.42.

EXAMPLE 7 Preparation of 5B-tert-butoxy-4,4a,5,6,7,8-hexahydro-1,

4afl-dimethyl-3-(N methylanilinomethylene)-2(3H)- naphthalenone (l-Rt-butoxy) To a. solution containing 2.78 g. (10 mmoles) of the formylcompound (prepared in Example 6) in 10 ml. methanol is added 1.17 g. (11mmoles) N-methylaniline. The mixture is warmed slightly and then allowedto stand at room temperature overnight. The solvent and excess anilineare removed under reduced pressure to leave 3.5

l l g. of orange-yellow oil. This material is crystallized fromnitromethane and has melting point 77.579 C.

EXAMPLE 8 Preparation of 3',4,8',8'a-tetrahydro-S',8'a-dimethyl-7'-(N-methylanilinomethylene)-spiro[1,3 dioxolane-2,1' (2'I-I) -napthalen]-6 (TH) -one crystalline product weighs 165.35 g., melting point 152EXAMPLE 9 Preparation of 5 'a-allyl-3 ',7,8 ',8a-tetrahydro-5 '5,S'afldimethyl-7'-(N methylanilinomethylene) spiro[1,3-dioxolane-2,l'(2'H) naphthalen] 6(5H)-one (II =ethylenedioxy) To astirred solution of 3.53 g. (0.01 mole) of material (prepared in Example8) in 125 ml. dry t-butanol under nitrogen is added 5.6 g. potassiumt-butoxide. The solution is heated under reflux for 30 minutes. Themixture is cooled to room temperature and 6.05 g. (0.05 mole)redistilled allyl bromide added dropwise. The solution is then heatedunder reflux for 1 hour. After cooling, the solution is poured intowater, acidified with 2.5 M sodium dihydrogen phosphate and extractedwith ether. The extract is washed with water, dried and the solventremoved under reduced pressure to give the crude product (4.35 g.).Crystallization from absolute ethanol gives 2.24 g. (57%) of desiredproduct, melting point 147.5l49.5 C.

Calcd. for C H N (percent): C, 76.30; H, 7.94; N, 3.56. Found (percent):C, 75.98; H, 7.81; N, 3.83.

EXAMPLE 10 Preparation of. 'a-allyl-3',7',8',8a-tetrahydro-5 3,8'a5-dimethyl-spire 1,3-dioxolane 2, 1(2'H) -naphthalen] 6'(5H)-one (HIR=ethylenedioxy) A mixture containing 30.65 g. (0.078 mole) anilinecompound, (prepared in Example 9) in 160ml. 2-ethoxyethanol and 160 ml.water containing 35.0 g. potassium hydroxide is heated at reflux undernitrogen for 4 hours. The mixture is cooled, diluted with water andextracted with ether. The organic phase is Washed successively withwater, dilute hydrochloric acid, water and brine, dried and evaporated.The residue is crystallized from hexane to give the product meltingpoint 67.5-68.5 C.

Calcd. for C H O (percent): C, 73.88; H, 8.75. Found (percent): C,73.73; H, 8.64.

EXAMPLE 11 Preparation of5'a-allyl-3',7,8',8a-tetrahydro-5'fl,S'afidimethyl-spiro[ 1,3-dioxolane2,1(2'H)-naphthalen] 6 '(5'H)-one (III R=ethylenedioxy) To a solutioncontaining 47.0 g. enone (prepared in Example 4) in 500 ml. dryt-butanol is added under nitrogen with stirring 56 g. potassiumt-butoxide. The mixture is heated under reflux for 2 hours. The solutionis cooled to room temperature and 29 g. allyl bromide is added dropwise.After stirring a further /2 hour at room temperature, the mixture ispoured into Water and extracted twice With ether. The ether extract iswashed twice With water, dried and evaporated. The residue iscrystallized from hexane to give 30.9 g. allyl compound identical withthat formed in Example 10.

When the starting material contains'the t-butoxy or tetrahydropyranyloxygroup instead of ethylenedioxy the corresponding t-butoxy andtetrahydropyranyloxy products are obtained.

EXAMPLE 12 To a solution containing 27.6 g. of the allyl compound(prepared in Example 10), in 450 ml. tetrahydrofuran is added a solutioncontaining 12.8 g. sodium chlorate in 200 ml. water and 2 ml. of anaqueous solution of osmium tetroxide (1 mmole/S ml. Water). Afterstanding overnight at room temperature, this solution is combined with asimilar one and shaken with a solution of 575 g. sodium sulfite in 2.5liters of water. The mixture is extracted twice with methylene chlorideand the extract Washed with saturated brine. The organic phase is driedand concentrated. The residue is crystallized from ether to give 49.9 g.hemiketal, melting point 122136 C. as a mixture of stero isomers. Asecond crop of crystals Weighted 4.4 g.

Similar reaction with ether the tetrahydropyranyl ether or t-butyl etheryield the corresponding hemiketal as oils.

EXAMPLE 13 Preparation of 5'a-formylmethyl-3,7',8,8'a-tetrahydro5',8,8a,8 dimethyl-spiro[l,3 dioxolane 2,1'(2H) naphthalen] 6- (5 'H-one (VI R ethylenedioxy) To a solution containing 49.9 g. of thehemiketal (prepared in Example 12), in 480 ml. tetrahydrofuran is addedwith stirring and cooling 74.1 g. sodium metaperiodate in 480 ml. Water.Stirring is continued overnight at room temperature. The mixture is thenshaken with a solution containing 230 g. sodium sulfite and extractedwith methylene chloride. The extract is washed with saturated brine,dried and evaporated. The residue is crystallized from ether-hexane togive 38.2 g. of the above aldehyde, melting point 6162.5 C. identicalwith the aldehyde prepared by ozonolysis of (III).

EXAMPLE 14 Preparation of S'a formylmethyl-3',7',8',8'a-tetrahydro-5fi,8aB-dimethylspiro[1,3,dioxolane 2,1(2'H) naphthalen]-6'(5H)-one (VIR=ethylenedioxy) In a gas wash bottle with fritted disc on the end ofthe inlet tube is placed 2.76 g. (0.01 mole) of allyl compound (preparedin Example 11) and 5.2 ml. pyridine and 36 ml. chloroform added. Thesolution is cooled to 20 C. and 1.3 equivalents of ozone passed into thesolution. Excess ozone is then removed in a stream of nitrogen. Then amixture of 5.48 ml. water, 5.45 ml. acetic acid and 10.76 ml. pyridineis added to the solution. While keeping the temperature of the solutionbelow 0, 3.28 g. zinc powder (which had been washed first with 2 Nacetic acid followed by water) is added in small portions With shakingand cooling during about 20 minutes. The mixture is filtered into aseparatory funnel and diluted With benzene and water. The aqueous phaseis reextracted with benzene. The combined organic phases are Washedsuccessively with water, saturated sodium bicarbonate, With 1.5 Nphosphoric acid, saturated sodium bicarbonate and water. The benzenesolution is dried and evaporated to leave the above aldehyde (2.0 g.).

EXAMPLE 15 Preparation of 2, 3'a,4',5,5a,7,8,9b octahydro 2'-(m-methoxyphenyl) 5'a/i,9b,8 dimethyl spiro[l,3- dioxolane2,6'(l)naphtha[2,1 b]furan] 3'a 01 (VII R=ethylenedioxy and R H) Alloperations are carried out under dry nitrogen. To 1 g. of magnesium isadded enough dry tetrahydrofuran to cover the metal. A few drops ofdibromoethane is added to initiate the reaction. Then 5.61 g. (0.03mole) mbromoanisole is added at such a rate as to maintain a reactionmixture temperature of about 50. The mixture was then stirred at 50 fora further 0.5 hour. The Grignard reagent is transferred to a droppingfunnel using dry tetrahydrofuran to complete the transfer. Half of thissolution is then added dropwise to the crude aldehyde (prepared inExample 14) in 40 ml. dry tetrahydrofuran. After the addition, thereaction mixture is stirred at room temperature for 1 hour. The excessreagent is destroyed by the addition of 40 ml. of a 2.5 M sodiumdihydrogen phosphate and after stirring for 10 minutes, the mixture isdiluted with ether and water. The ether extract is washed twice withwater followed by saturated brine, dried and evaporated. The residue iscrystallized from ether to give in three crops 1.2 g. of the abovehemiketal, melting point 148-155 C.

EXAMPLE 16 Preparation of 3',7',8',8'a-tetrahydro 5'04(m-methoxyphenacyl)-5B,8'ap dimethyl 7 (N-methylanilinomethylene)spiro[1,3 dioxolane-2,1'(2H) naphthalen]-6(5H)-one (VIIIR=ethylenedioxy) In a flask equipped with stirrer, condenser (with drynitrogen inlet) and dropping funnel are placed 52.95 g. (0.15 mole) of3,4,8',8'a-tetrahydro 5,8a dimethyl- 7 (N methylanilinomethylene)spiro[1,3-dioxolane- 2,1(2H)-naphthaden] 6(7'H) one (prepared in Example8) in 600 ml. dry dimethoxyethane and 16.65 g. sodium hydride (54%suspension in mineral oil). The mixture is heated with stirring underreflux in a nitrogen atmosphere for two hours. This mixture is cooledand a solution of 51.45 g. (0.225 mole) of m-methoxyphenacyl bromide inabout 500 ml. dry dimethoxyethane is added very slowly at roomtemperature. After the addition, the solution is stirred overnight atroom temperature. Water is added to the solution and the reactionmixture poured into water, acidified with 2.5 M sodium dihydrogenphosphate and extracted with methylene chloride. The extract is washedwith water, dried and evaporated. The residue is crystallized fromacetone to give 45.3 g. (60%) of desired product, melting point169.5170.5 C.

Calcd. for C H O N (percent): C, 74.23; H, 7.03; N. 2.79. Found(percent): C, 74.39; H, 7.20; N, 2.36.

A similar experiment is run using the same quantities as above. The onlymodification made is that the phenacyl bromide isadded to the reactionmixture at ice-bath temperature during 4.2 hours. The yield of productis 63.9 g. or 84.7%.

EXAMPLES 17 and 18 Preparation of 3',7',8,8a-tetrahydro 5'0:(m-methoxyphenacyl)-5'B,8'a[3 dimethyl spiro[1,3 dioxolane- 2,1(2H)naphthalen] 6' (S'H) one (X=ethylenedioxy), and 3,7',8,8'a tetrahydro 7'(hydroxymethylene) S'u (m methoxyphenacyl) 5;3,8'afidimethyl, spiro[1,3dioxolane 2,1'(2'H)naphthalen]- 6'(5) one (IX R=ethylenedioxy) To asolution of 91.8 g. (0.183 mole) of the anilino compound (prepared inExample 16) in 610 ml. 2-ethoxyethanol is added 610 ml. water containing258 g. potassium hydroxide. The mixture is heated at reflux undernitrogen for 6 hours and then cooled overnight. Two liters of water areadded and the solution extracted with ether. The ether extract issuccessively washed with water, cold 2 -N hydrochloric acid and water.The extract is dried and the solvent evaporated. The residue (X,R=ethyleneidoxy) on trituration with ether and recrystallization fromacetone-hexane has melting point 121-122 C.

Calcd. for C H O (percent): C, 71.85; H, 7.34. Found (percent): C,71.59; H, 7.34.

The aqueous phase from the first ether extraction above is acidifiedwith ice-cold 2 N hydrochloric acid and extracted with methylenechloride. The extract is washed with water and brine, dried andevaporated. The residue on trituration with ether at 5 C. andrecrystallization from methanol gave the formyl compound, melting point157160.5 C. (IX, R=ethylenedioxy).

Calcd. for C H O (percent): C, 69.88; H, 6.84. Found (percent): C,69.57; H, 6.89.

EXAMPLE 19 Preparation of 3,7',8,8'a-tetrahydro Su (m-methoxyphenethyl)5 8,8aB dimethyl spiro[1,3-dioxolane- 2,1"(2H) naphthalen] 6(5'H) one(XI, R=ethylenedioxy) (A) A solution containing 10.0 g. (0.026 mole) ofthe diketone (X, R=ethylenedioxy) (Example 17) in 150 ml. glacial aceticacid is reduced with hydrogen at C. in the presence of 1 g. 5% palladiumon carbon. The initial pressure is 51.8 p.s.i. Reduction is complete in3 hours. The solution is cooled, the catalyst removed by filtration andthe solvent removed under reduced pressure. The residue (i.e., crudeproduct [XI, R=ethylenedioxyl1) is used directly for the preparation ofthe naphthalenedione (XV, Rqthylenedioxy) (B) A solution containing 4.5g. of hemiketal (prepared in Example 15) in 50 ml. glacial acetic acidis reduced with hydrogen at 70 and 50 p.s.i. in the presence of 200 mg.5% palladium on carbon. Reduction is compared in Example 15 in 50 ml.glacial acetic acid is reevaporated to leave crude ketone (XI,R=ethylenedioxy) of sufficient purity for further transformations.

(C) Similarly, reduction of the corresponding t-butoxy ortetrahydropyranyloxy ethers (VII) yields the corresponding ketones (XI,R=t-butoxy and tetrahydropyranyloxy) EXAMPLE 20 A solution containing 10g. of the di-ketone (prepared in Example 17) (X, R=ethylenedioxy) in 180ml. methanol is reduced catalytically at 60 C. and an initial pressureof 50 p.s.i. in the presence of 1.0 g. 5% palladium on carbon. Thereduction is complete in 2 hours. The mixture is cooled, and filteredand the solvent removed under reduced pressure. The residue is a mixtureof hemiketal (VII, R'=H) and the mixed ketal (VII, R'--=CH The crudereduction product is dissolved in a mixture of 108 ml. acetic acid and36 ml. water and the solution heated on the steam bath for 1 hour. Thereaction mixture is poured into water and extracted with ether. Theextract is washed with water and saturated sodium bicarbonate solution.The ether is dried, the solvent evaporated and the residue crystallizedfrom acetone-hexane to give product (XII), melting point 1355-1385.

Calcd. for C H O (percent): C, 73.66; H, 7.66. Found (percent): C,73.60; H, 7.59.

By concentration of the mother liquors the second crystalline isomer, isobtained. Recrystallization of this material from acetone-hexane givesproduct, melting point 132.5133.5 C.

EXAMPLE 21 Preparation of 3,7,8,8a tetrahydro 5a(fi-hydroxy-mmethoxyphenethyl) 55,8afl dimethyl-, 1,6(2H,5H)-naphthalenedione, acetate (XIII) A solution containing 5.0 g. (0.0146mole) of the hemiketal (XII) (prepared in Example 20) in ml.

acetic acid and 40 ml. acetic anhydride is heated under reflux for 1hour. The solvents are then removed under reduced pressure, the residuedissolved in toluene and this also removed under reduced pressure. Theresidue compound (XIII) is used without further purification.

EXAMPLE 22 Preparation of 3,7,8,8a-tetrahydro-5a-(m-methoxystyryl)- 5fi,8a;3-dimethyl-1,6(2H,5H) -naphthalenedione (XIV) A solutioncontaining 2.0 g. p-toluenesulfonic acid in 170 ml. benzene is heatedunder reflux under a Dean- Stark Water separator filled with anhydrouscalcium sulfate for minutes. The crude acetate prepared in Example 21 inml. benzene is then added and refluxing continued for 1 hour. Thesolution is cooled, diluted with ether and washed with saturated sodiumbicarbonate. The organic phase is dried and veaporated. The residue iscrystallized from methanol to give 1.8 g. product (XIV).Recrystallization of this material from methanol gives 1.5 g., meltingpoint 91-92 C.

Calcd. for C H O (percent): C, 77.75; H, 7.46. Found (percent): C,77.57; H, 7.51.

EXAMPLE 23 Preparation of 3,7,8,8a-tetrahydro-5a-(m-methoxyphem yl) 5fl,8afl-dimethyl 1 ,6 2H,5 H) -naphalenedione (XV, R220) The crudeproduct (XI) prepared in Example 19 above is heated on the steam-bathwith 20 ml. water and enough acetic acid to give a homogeneous solutionfor 1 hour. After standing at room temperature overnight, the solutionis diluted with water and extracted with ether. The ether extract isWashed with water and then saturated sodium bicarbonate solution. Theextract is dried and the solvent removed. The residue crystallized frommethanol to give 5.0 g. product (XV, R =O), melting point 68- 70 C.

EXAMPLE 24 Preparation of 3,7,8,8a-tetrahydro-5u-(m-methoxyphenyl)5fl,8a;3 dimethyl 1,6(2H,5H)-naphthalenedione (XV, R =O) A solutioncontaining 324 mg. (1 mmole) of compound (XIV) (prepared in Example 22)in 15 ml. ethanol is reduced catalytically at room temperature andatmospheric pressure in the presence of mg. 5% palladium on carbon. Thecatalyst is removed by filtration and the solvent removed under reducedpressure. After standing 'for sometime, the product crystallizes.Crystallization from a mixture of ether and hexane gives product, (XV, R=O), melting point 6971 C.

Calcd. for C H O (percent): C, 77.27; H, 8.03.

Found (percent): C, 77.39; H, 7.93.

EXAMPLE 25 Preparation of 1,2,3a,4,5,5a,6,7,8,9bdecahydro-Z-(mmethoxyphenyl)-5a;3,9b,8-dimethyl, naphtho[2,1-b]furan-3a,6;9-diol (XIV) To a solution containing 5.0 g. (0.015 mole)ketone (XII) (prepared in Example 20) in 100 ml. absolute ethanol isadded 2.0 g. sodium borohydride. The reaction is allowed to proceed atroom temperature with intermittent swirling for 15 minutes. The mixtureis then poured into water and extracted with ether. The ether extract iswashed with' water, saturated brine, dried and evaporated.

The residue is crystallized from acetone-hexane to give productcompound(XVI), melting point 141-l48 C.

Calcd. for C H O (percent): C, 73.22; H, 8.19. Found (percent): C,73.05; H, 8.13.

16 EXAMPLE 26 Preparation of3,4,4a,5,6,7-hexahydro-5B-hydroxy-1u-(mmethoxyphenyl)1,8,4afl-dimethyl-2 1H) -naphalenone (XVII) A solution containing 688mgs. of the hemiketal (prepared in Example 25) in 18 ml. glacial aceticacid is reduced with hydrogen at 45 p.s.i. and in the presence of 100mgs. 5% palladium on carbon. The reduction is complete in 2 hours whenthe mixture is cooled, the catalyst removed and the solvent evaporatedunder reduced pressure. The material (XV, R =OH or XVII) is ofsufficient purity for conversion by oxidation to compound (XV, R =O) orreduction to compound (XVIII).

EXAMPLE 27 Preparation 3,4,4a,5,6,7 hexahydroSB-hydroxy-M-(mmethoxyphenethyl) 1fi,4a,8-dimethyl-2(1H)-napthalenone(XVII) (A) To a solution containing 1.63 g. of the enedione (prepared inExample 23) in 25 ml. ethanol is add ed with stirring 0.5 g. sodiumborohydride. Stirring is continued for 15 minutes and the mixture thendiluted with a large volume of water. The solution is extracted withether, the extract washed with water, dried and evaporated. The residuecompound (XVII), an oil, is used without further purification.

(B) A solution containing 688 mgs. of the hemiketal (prepared in Example25) in 18 ml. acetic acid is hydrogenated at 70 C. .and 50 p.s.i. Afterthree hours the catalyst is removed and the solvent evaporated to give aresidue identical to that described above compound (XVII).

EXAMPLE 28 Preparation of3,4,4a,5,6,7,8,8w-octahydro-Sfl-hydroxylMm-methoxyphenethyl) 1fl,4a}8dimethyl-2(1H)- naphthalenone (XVIII) A solution containing 1.38 g. ofcrude unsaturated keto alcohol (XVII) prepared as in Example 27 in 20ml. ethanol is reduced at 70 C. with hydrogen in the presence of 200 mg.5% palladium on carbon. After 20 hours, the catalyst is removed and thesolvent evaporated. The residue containing the above named product(XVIII) is used without further purification.

EXAMPLE 29 Preparation of3,4,4aa,7,8,8a-hexahydro-Sa-(m-methoxyphenethyl) -5fi,8a;3-dimethyl1,6(2H,5H)-naphthalenedione (XIX) The crude keto alcohol (XVIII)prepared in Example 28 is dissolved in 20 ml. acetone and cooled to 0.Jones reagent is then added dropwise with stirring until a permanentbrown color is obtained. The solution is stirred for 15 minutes at roomtemperature and then poured into water and extracted with ether. Theextract is washed with Water, dried and evaporated. The residue isrecrystallized from ether-hexane to give 640 mg. trans-dione, (XIX),melting point 86-885 C.

EXAMPLE 30 Preparation of 3-methoxy-SB-methyl-D-homoestra- 1,3,5( 10) ,91 1 )-tetraen-17a-0ne (XX) To 328 mgs. of the trans-dione (XIX)(prepared in Example 29) in 6 ml. ethanol is added 3 ml. concentratedhydrochloric acid and the solution refluxed for 20 minutes. The mixtureis diluted with water and extracted with water, dried and evaporated.The residue is crystallized from acetonitrite to give the product (XX),melting point 1505-1525 C.

1 7 EXAMPLE 31 (A) To 1 g. of the diketone (XV, R =O) (prepared inExample 23) in 18 ml. ethanol is added 6 ml. concentrated hydrochloricacid and the mixture heated under reflux for 20 minutes. The solution iscooled, poured into water and extracted with ether. The ether is washedwith water, dried and evaporated. The residue, (XXI) is used directlyfor the preparation of the following compound (XXII).

(B) Approximately 2 ml. of liquid hydrogen fluoride are placed in apolyethylene tube containing a magnetic stirrer and immersed in anice-water bath. T this is added 1 g. diketone (XV) (prepared in Example23) and the mixture stirred for minutes. Methylene chloride is thenadded and the solution washed twice with water followed by saturatedsodium bicarbonate solution. The organic phase is dried and the solventremoved under reduced pressure. The residue XXI is used directly for thepreparation of compound (XXII).

EXAMPLE 32 Preparation of 3-methoxy-SB-methyLD-homoestra- 1,3,5 10) ,9 11 14-pentaen-17afl-ol (XXII) (A) The crude product (XXI) (prepared inExample 31) above using concentrated hydrochloric acid to effect thecyclization is dissolved in 10 ml. ethanol and 500 mgs. sodiumborohydride added. The solution is allowed to stand at room temperaturewith intermittent swirling for 7 hours. The mixture is diluted withwater, acidified with concentrated hydrochloric acid and extracted withether. The ether extract is washed twice with water followed bysaturated sodium bicarbonate solution, dried and the solvent evaporated.The residue compound (XXII) is used directly for the preparation of theacetate compound (XXIII). The product (XXII) has, melting point 96-97 C.

Calcd. for C H O (percent): C, 81.27; H, 8.44. Found (percent): C,81.30, H, 8.54.

EXAMPLE 3 3 Preparation of 3-methoxy 8,8 methyl-,D-homoestra- 1,3,5 10),9 1 1 ,14-pentaen-17aB-o1 acetate (XXIII) (A) The crude product (XXII)(prepared in Example 32) above is allowed to stand overnight with 10 ml.acetic anhydride and 2 ml. pyridine. The solvents are then removed underreduced pressure and the residue dissolved in ether. The ether extractis washed with dilute hydrochloric acid, water and saturated sodiumbicarbonate, dried and the solvent evaporated, The residue is filteredthrough alumina in benzene. The benzene is evaporated and the residuecrystallized from pentaene then hexane to give the acetate, compound(XXIII), melting point 133.5-134 C.

Calcd. for 0 1-1 0 (percent): C, 78.37; H, 8.01. Found (percent): C,78.59; H, 8.12.

. EXAMPLE 34 Preparation of 3-methoxy-8B-methyl-,D-homo-9E-estra- 1,3,510),l4-tetraen-17ap-ol, acetate (XXIV) A solution containing 352 mgs. (1mmole) of diene (XXIII) (prepared in Example 33) in 20 ml. glacialacetic acid is catalytically reduced at room temperature and atmosphericpressure in the presence of 100 mgs. 5% p lladium on carbon. Thecatalyst is removed by filtration and the solvent evaporated. Theresidue in benzene is filtered through a plug of activated magnesiumsilicate and the solvent then removed under reduced pressure. Theresidue is crystallized from acetone-hexane to give prod- 'uct (XXIV),melting point 149-155 C.

Calcd. for C I-I O (percent): C, 77.93; H, 8.53. Found (percent): C,77.69; H, 8.53.

18 EXAMPLE 35 Preparation of 3-methoxy-8m-methyl-D-homo 9g estral,3,5(lO),l4-tetraen-17afl-ol (XXV) To 6.0 g. of the acetate (XXIV) (preparedin Example 34) dissolvedin 15 0 ml. ethanol is added 50 ml. 2 Npotassium hydroxide solution and the mixture refluxed for 2 hours. Thesolution is diluted with water, acidified with 2 N hydrochloric acid,and extracted with ether, The extract is washed with water and sodiumbicarbonate solution, dried and evaporated. The residue is crystallizedfrom acetone-hexane to give 3.6 g. of the alcohol, (XXV), melting point135-136 C.

EXAMPLE 36 Preparation of 3-methoxy-SB-methyl-D-homo 9.5 estra-1,3,5(10)-trien-l7a,8-ol (XXVI) A solution containing 312 mg. of theunsaturated alcohol (XXV) (prepared in Example 35) in 18 ml. ethanol isreduced with hydrogen at 70 C. and 50 p.s.i. in the presence of mg. 5%palladium on carbon. After 20 hours, the catalyst is removed and thesolvent evaporated. The residue is dissolved in benzene and filteredthrough a plug of activated magnesium silicate. The solvent is removedand the residue crystallized from acetone-hexane to give 225 mg. product(XXVI), melting point l28131 C. The material is recrystallized fromacetonitrile to yield a solvate, melting point -132" C.

EXAMPLE 37 Preparation of3,4,4afl,7,8,8a-hexahydro-5a(m-methoxyphenylethyl) -5/3,8a13-dimethyl-l,6 2H,5 H -naphthalenedione (XXVII) A solution containing 652 mgs. ofthe enedione (XV, -R =O) (prepared in Example 24) in 18 ml. absoluteethanol is reduced with hydrogen at 75 C. and 50 p.s.i. in the presenceof 100 mg. 5% palladium on carbon. After shaking for 22 hours, themixture is cooled and the catalyst removed by filtration. Fractionalcrystallization gives the cis isomer, cubes, melting point 74-75 C.compound (XXVII) as the major product. The trans isomer, needles,melting point 87-88 C. is also indicated in small quantity.

EXAMPLE 38 Preparation of 3-methoxy-8,8-methyl-D-homo-l4fiestra-1,3 ,410) ,9 1 1 -tetraen-17a-one (XXVIII) To 5 ml. anhydrous hydrogenfluoride in a polye thylene tube cooled to 0 with stirring is added 200mgs. of the cis-dione compound (XXVII) (prepared in Example 37). Afterstirring for 5 minutes, the solution is diluted with methylene chlorideand poured into ice-water. The organic phase is washed with aqueousbicarbonate solusolution, dried and evaporated. The residue iscrystallized from acetone-hexane to give 123 mgs. compound (XXVIII).Recrystallization from acetonitrile gives sample melting point 139140 C.

Alternatively the cyclization can be carried out with strong acid. To asolution containing 200 mg. dione (XXVII) (prepared in Example 37) in 3ml. ethanol is added 1 ml. concentrated hydrochloric acid and thesolution refluxed for 20 minutes. The cold solution is diluted withwater and extracted with ether, the extract washed twice with water,dried and evaporated. The residue is crystallized from acetone-hexane togive mg. product (XXVIII) identical with that described in the paragraphabove.

EXAMPLE 39 Preparation of3-methoxy-8B-methyl-D-hom0-9'-estral,3,5(l0)-trien-17a-one (XXIX) (A) Toa stirred solution containing 314 mg. of the alcohol compound (XXVI)(prepared in Example 36) in 25 ml. acetone at 0 is added dropwise Jonesreagent until a permanent brown-colored solution is obtained.

The solution is stirred at room temperature for 15 minutes and thenpoured into water and extracted with ether. The extract is washed withWater, dried and evaporated. The residue is crystallized fromacetone-hexane to give 265 mgs. ketone (XXIX), melting point 148150 C.

(B) A solution containing 310 mg. 3-methoxy-8[3-Inethyl-D-homoestra-1,3,5(10),9(11)-tetraen 17a one Compound (XX)(prepared in Example 30) in 15 ml. acetic acid is reduced with hydrogenat room temperature and atmospheric pressure in the presence of 100 mg.5% palladium on carbon. After 1 hour, the catalyst is removed and thesolvent evaporated. The residue is crystallized from acetone-hexane togive 248 mg. product, melting point 149'-l50 0, identical with thatdescribed in paragraph A.

EXAMPLE 40 Preparation of 17au-ethynyl-3-methoxy 8p methyl-D-homo-9-estra-1,3,5(10)-trien-17a;8-ol (XXX) A stirred suspension ofsodium hydride (800 mg., 54%) in 90 ml. dry dimethyl .tormamide iscooled to 10 C. and dry acetylene bubbled through the solution EXAMPLE41 Preparation of 17aa-ethynyl-3-methoxy 8 8 methyl-D- homoestra-1,3,510) ,9 1 1 -tetraen-17aB-ol (XXXI) Dry acetylene is bubbled into astirred suspension of sodium hydride (200 mg., 54%) in 30 ml. drydimethyl formamide at 10 C. for one hour. Then 310 mgs. ketone compound(XX) (prepared in Example 30) in ml. dry dimethyl formamide is addeddropwise. Stirring and addition of acetylene at -10 C. is continued ifOI3 hours. Water is carefully added and when diluted acidified with 6 Nsulfuric acid and extracted with ether. The ether is washed twice withwater, dried and evaporated. The residue is crystallized fromacetonehexane. The product compound (XXXI) crystallizes as an acetonesolvate, melting point 156.5158 C.

EXAMPLE 42 Test for estrogenic activity Immature female Wistar originrats are 19 to 21 days of age and are employed as the test animal todetermine estrogenic activity of candidate compounds. Test compounds aregiven by subcutaneous injections once daily for three successive days in0.2 ml. of injection vehicle. This injection vehicle is:

0.5 gm. carboxymethylcellulose (low viscosity) 0.4 gm. Tween 80 0.9 gm.sodium chloride 10.0 ml. polyethylene glycol (Carbowax 300) 90.0 ml.distilled water Twenty-four hours after the third injection the rats aresacrificed, the uteri removed and disected free from the ovaries,oviducts and mesentery. Each uterine horn is split longitudinally andthe uterine fluid bottled dry. The uteri are Weighed to the nearestmilligram on a balance. Ten rats are used for each treatment. Increaseduterine weight over the control (untreated) uteri indicates estrogenicactivity. all animals receive a commercial laboratory animal ration adlibitum and fresh Water is available at all times While on test. The:following table summarizes the estrogenic activity of the presentcompounds.

TABLE Compound Efiective Date OH 0.5 mg. estrogen/rat/day. (\I -CEGHCHsO- OH Do. A "CECE E Fl) D0.

0 Do. p H

0G0 CH3 0. mg. estrogen/rat/day.

What is claimed is:

1. A compound selected from the group consisting of compounds of theformulas:

wherein P is a member selected from the group consistmg of CHaO- OH 0 IH 2. A compound of the formula:

CHsO- wherein Q is a member selected from the group consisting of I(II-435011 and the hydrogen is cis or trans to the C methyl group.

and

4. The compound in accordance with claim 13-methoxy-8/3-methyl-D-homo-9g-estra-1,3,5(10)-trien-17afl-ol.

5. The compound in accordance with claim 1,3-mcthoxy-8B-methyl-D-homo-9g-estra-1,3,5(10)-trien-17a-one.

6. The compound in accordance with claim 1, 172methynyl 3 methoxySfl-methyl-D-homo-9-estra-1,3, 5 10)-trien- 172113-01.

7. The compound in accordance with claim 1, 3-rnethoxy 8B methylD-homo-l4fl-estra-1,3,5(10),9(11)- tetraaen-17a-one.

8. The compound in accordance with claim 1, 1730(- ethynyl 3 methoxy 8Bmethyl- D-homoestra-L3, 5 10) ,9( l 1)-tetraen-17a}3-ol.

References Cited UNITED STATES PATENTS 3,076,023 1/1963 Kaspar et al260586 3,318,925 5/1967 Anner et a1. 260397.4 3,318,928 5/1967 Anner eta1 260-397.5 3,391,170 7/1968 Hughes et a1. 260-39745 OTHER REFERENCESChemical Abstracts, vol. 62 (1965), col. 3892a (Abstract of FrenchPatent, M2743, Sept. 21, 1964).

ALEX MAZEL, Primary Examiner J. H. TURNIPSE-ED, Assistant Examiner US.Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,565,958 Dated February 23, 1971 Inventofls) Mgrirms LOS It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 1 line 5 insert "Assignor to American Cyanamid Company, Stamford,Connectix a Corporation of Maine".

Signed and sealed this 15th day of June 1971 (SEAL) Attest:

EDWARD M.FLETGHER,JR. WILLIAM E. SCHUYLER, Attesting OfficerCommissioner of Patent

